In general, small doses of nicotine have a stimulating action on the central nervous system whereas large doses depress. However, studies of the central nervous actions of nicotine have not yet fully established confident correlations of the action of this drug with central levels. For this reason it has not been possible to consider its actions on the basis of a strictly neuroanatomical outline.
Mammalian studies also indicate that conditioned reflexes may be inhibited by nicotine. It does appear that nicotine abolishes the relationship between the strength of the conditioned stimulus and the response, for example, salivation. Increasing the dose of nicotine results in progressive inhibition, culminating in total loss of conditioned food reflexes. While the mechanism of action of nicotine upon conditioned reflexes has been speculated upon in the literature, there is presently no certainty as to whether a specific site or mode of action is involved or whether one is dealing here with a general depressant effect upon animal behavior as a whole. In some experiments, nicotine caused marked inhibition of conditioned reflexes with increase of secretory responses to the unconditioned stimulus of feeding. This has been held to prove that certain doses of nicotine have a stimulating influence on the centers of unconditioned reflexes. Thus, it has been said that the effect of large doses of nicotine is to inhibit cerebral cortical function and not cause paralysis of the "center" of salivation. Although suggestive of the need for further investigation and the line which such investigations might take, these studies do not help greatly in localizing the neurophysiological mechanisms involved.
With respect to learning experiments in animals, a somewhat similar unsatisfactory situation exists. Nicotine appears to reduce the performance of white mice in a maze, with regard to both running time and errors in acute and chronic experiments. However, these effects on performance are probably not due to any specific interference with the learning process itself but may be explained on the basis of non-specific effects upon the general health of the animal. There does not yet seem to be any conclusive evidence, either in animals or in man, of a specific effect of nicotine upon learning.
As has been pointed out, a feature of the reported experiments on the effect of nicotine upon sensorimotor functions is the very high concentrations of nicotine solutions used in topical applications to the brain surface or local injections within the brain. These concentrations were so high that they could never be reached by systemic administration of even lethal doses; moreover, the concentrations were often sufficiently high to produce local non-specific tissue necrosis at the site of application. Therefore, it is doubtful that these experiments on sensorimotor functions gave results that offer indication of the actual pharmacological action of nicotine.
It has been found that visual action potentials in the optic lobes evoked by flashing lights in the eyes in frogs are abolished within a few minutes by local application of nicotine to the exposed optic lobes. These studies and the others that have been reviewed indicate the breadth of possible fields of study of the effects of nicotine upon brain potentials. Turning to electroencephalographic changes in mammals, nicotine administration causes typical "grand mal" seizure patterns if sufficiently large doses are given. Smaller doses appear to cause only prolonged desynchronization. With somewhat larger doses, there may be tonic and clonic contractions as well as muscular fibrillation and the appearance in the EEG tracing of convulsive patterns. Very likely the desynchronizing effect of nicotine is due to excitation of the reticular formation. The convulsive effect has been ascribed to a general state of excitation, probably including cortical neurones. With even larger doses, EEG changes characteristic of an arousal reaction are obtained. With regard to the electroencephalographic changes in the human subject associated with cigarette-smoking, namely an increase in the dominant alpha rhythm, it appears that this is the result of psycho-physiologic changes relative to the act of smoking rather than to physiologic or metabolic effects from specific substances present in cigarette-smoke.
Tremor, one of the highly characteristic effects of nicotine both in man and in lower animals, is undoubtedly a result of central nervous stimulation, although nicotine does have a demonstrable effect directly upon skeletal muscle. Tremor is usually followed by convulsions in animals if the dose of nicotine is sufficient. The site of the convulsive action of nicotine has been variously localized. For example, it has been argued that the antinicotinic effect of ethopromazine and other drugs is at the level of the reticular substance and probably involves a cholinergic mechanism, such as blocking acetylcholine actions centrally. It has been held also that the convulsive action of nicotine is due to alteration in hippocampal excitability, or that it acts at the level of the diencephalon, or that the convulsive effect is due to a general state of excitation probably including cortical levels. The upper levels of the central nervous system are probably broadly implicated as sites of the convulsive action of nicotine.
With regard to the paralysis which is seen to follow the convulsions in experimental nicotine poisoning, mechanisms similar to those involved in convulsions seem to be present. The site of action of nicotine in causing catalepsy has not been identified with certainty and further study of this matter is required.
As to medullary functions, it has been stated that we possess practically no reliable facts about the effects of nicotine on the brain stem (or the cerebellum or spinal cord) in man. Nausea and vomiting are the most common symptoms and signs of acute nicotine poisoning in man, and the localization of the emetic action of nicotine has been the subject of considerable study. Small doses of nicotine are emetic while large doses fail to cause vomiting and in fact may even be anti-emetic. As to the site of the emetic action, investigations in animals in general indicate that central as well as peripheral factors are involved. Small doses of nicotine applied topically to the vomiting center increase its reflex excitability. However, it may be that nicotine does not act directly upon the vomiting center in exerting its emetic action. Ablation of the emetic chemoreceptor trigger zone (CT zone) in the area postrema of the medulla oblongata in dogs suffices for the protection of the animal against the emetic effect of nicotine. In cats, however, nicotine appears to act upon some peripheral locus as well as at the CT zone, since to prevent vomiting due to nicotine in this species it is necessary to carry out spinal deafferentation and mid-cervical vagotomy as well as CT zone ablation. It would therefore appear that both central medullary and afferent nervous mechanisms are involved.
With small and moderate doses of nicotine, it appears to have been established that the effects on respiration are reflexly mediated, and that lethal doses effect peripheral curare-like paralysis of the respiratory muscles. Similarly, the bradycardia produced by nicotine is of reflex origin, comparatively very large doses being required to stimulate the cardio-inhibitory center directly. There is virtually no evidence for a direct central origin of the cardio-accelerator effect of nicotine. Minimally effective doses appear to cause tachycardia reflexly through stimulation of chemoreceptors in such structures as the aortic and carotid bodies, while larger doses stimulate the sympathetic ganglia and the adrenal medulla. This mechanism also holds for the hypertensive effects of nicotine, although large doses may also produce vasomotor action of central origin.
The actions of nicotine upon cerebellar function are poorly understood. The report that topical application of nicotine to the exposed cerebellum causes disappearance of contraction of the nictitating membrane in response to cervical sympathetic stimulation warrants further investigation, since it provides another indication of the possible jurisdiction of the cerebellum over autonomic regulation. Further studies of the effects of nicotine upon cerebral cortical and cerebellar visceral control mechanisms are also indicated.
As to the effect of nicotine upon spinal functions, some studies indicate a stage of stimulation followed by a stage of inhibition or paralysis. However, it has been stated that the spinal depressant action of nicotine has been considerably overestimated in the literature. It has been held that nicotine does not have the blocking effect on synaptic transmission in the spinal cord that it shows on sympathetic ganglia and neuromuscular junctions. Other studies show that nicotine diminishes or abolishes the patellar reflex in animals while the flexor reflex is relatively unaffected. Monosynaptic activity appears to be depressed while multisynaptic activity is much less affected by nicotine, and may even be facilitated. It may indeed be that nicotine excites internuncial neurones, for example, the Renshaw cells. Analysis of the literature on spinal functions has exposed many unresolved discrepancies.